Neonatal hyperglycemia

INTRODUCTION — Glucose supply and metabolism are of central importance for growth and normal brain development in the fetus and newborn. Disorders in glucose availability or utilization can result in hypoglycemia or hyperglycemia.

The causes and management of neonatal hyperglycemia are reviewed here. Other related topics include:

●(See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)

●(See "Management and outcome of neonatal hypoglycemia".)

●(See "Neonatal diabetes mellitus".)

DEFINITION

Hyperglycemia — Various definitions are used for hyperglycemia in neonates. Two common definitions are blood glucose (BG) >125 mg/dL (6.9 mmol/L) or plasma glucose (the standard laboratory test) >150 mg/dL (8.3 mmol/L). However, levels in this range are frequently observed among neonates receiving glucose infusions, especially extremely preterm infants, and may not require intervention [1].

Most neonatologists define clinically important hyperglycemia as BG >180 to 200 mg/dL (10 to 11.1 mmol/L). At the authors’ institutions, this generally is the threshold used for intervention. (See 'Management' below.)

However, higher levels of hyperglycemia are required to produce hyperosmolality and osmotic diuresis. Plasma osmolality increases by 1 mosmol/L for each 18 mg/dL increase in plasma glucose concentration. Thus, a rise in glucose concentration from 110 to 200 mg/dL (6.1 to 11.1 mmol/L) only increases osmolality by 5 mosmol/L, which is a relatively small change.

Glucosuria — Glucose excretion in the urine in hyperglycemic neonates is determined by the degree of hyperglycemia and renal tubular reabsorptive capacity for glucose. Newborns have variable reabsorptive capacities for glucose, which may be particularly reduced in those who are critically ill or preterm.

The net effect is that glucosuria alone is not a good marker for hyperglycemia since it can occur at normal blood glucose concentrations. For example, in one study of sick preterm infants born at 25 to 33 weeks gestation, fractional glucose excretion varied widely and glucosuria was often seen at normal blood glucose concentrations [2]. These variations presumably are related to immaturity of the proximal tubule.

On the other hand, mild hyperglycemia may be associated with little or no glucosuria in infants with mature proximal tubules. This was illustrated in a study of newborns who were given glucose infusions; at a mean blood glucose concentration of 197 mg/dL (11 mmol/L), there was little glucosuria and no significant osmotic diuresis [3].

PATHOGENESIS — Hyperglycemia typically occurs when a newborn cannot adapt to parenteral glucose infusion by decreasing endogenous glucose production or increasing peripheral glucose uptake [4]. This is usually related to an associated clinical condition such as extreme prematurity or sepsis.

Normal glucose metabolism — In both term and preterm infants, the following observations of glucose metabolism are seen [4]:

●Hepatic glucose production is suppressed by infusion of glucose (with or without amino acids), hyperglycemia, and insulin.

●Glucose production is not changed by intravenous (IV) lipid infusion.

●Circulating insulin concentrations increase appropriately with hyperglycemia and increase hepatic and peripheral glucose uptake.

Pathogenesis of hyperglycemia in preterm infants — Hyperglycemia is more common in preterm infants compared with term infants. Although the mechanism(s) for the increased risk of hyperglycemia in preterm infants is uncertain, the following may be contributory factors:

●Impaired insulin response – Insulin responses may be inappropriately low in extremely low birth weight (ELBW) infants. In one study, 23 of 56 ELBW infants became hyperglycemic during IV glucose infusions that were incrementally increased to a maximum rate of 12 mg/kg per minute between days two and six of age [5]. Baseline insulin levels were similar in hyperglycemic and euglycemic infants, but only 15 of 23 hyperglycemic infants had a normal insulin response.

The inappropriate insulin response in hyperglycemic ELBW infants may be related to defective islet beta cell processing of proinsulin. In a study comparing 15 hyperglycemic to 12 normoglycemic ELBW infants during the first week of life, proinsulin levels were significantly higher in the hyperglycemic ELBW infants, who also needed higher insulin levels to reach euglycemia compared with normoglycemic infants [6].

●Incomplete suppression of glucose production – Suppression of hepatic glucose production in response to glucose infusion also varies in very immature infants and may be incomplete. In a series of 10 infants born at 25 to 30 weeks gestation, glucose production rates decreased from 4.3 to 1.4 mg/kg per minute as glucose infusion was increased from 1.7 to 6.5 mg/kg per minute [7]. Plasma concentrations of glucose and insulin also increased.

Proteolysis due to negative nitrogen balance, which occurs more commonly in the preterm infant, may also be a stimulus for inappropriate glucose production. For example, in ELBW infants, insufficient protein intake results in endogenous protein loss (proteolysis) in an effort to meet the basal metabolic needs of the infant.

●Increased secretion of counterregulatory hormones associated with stress – Secretion of epinephrine and cortisol in stressed infants may contribute to hyperglycemia. The role of stress was demonstrated in a report of metabolic responses to glucose infusion in preterm infants (weight 700 to 1550 g) [8]. Measurements were made before and after infusion in controls and in infants who required assisted ventilation and were considered stressed. Stressed infants had higher levels of glucose and of cortisol compared with controls and were more likely to have hyperglycemia (13 of 18 versus 1 of 12 infants). This difference was not due to decreased insulin or increased cortisol levels, because, among the stressed infants, insulin levels were higher and cortisol levels lower in the hyperglycemic compared with the euglycemic newborns. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus", section on 'Counterregulatory hormones'.)

CAUSES — In general, neonatal hyperglycemia is associated with a clinical condition, rather than a specific disorder of glucose metabolism, and it occurs mostly in infants receiving intravenous (IV) glucose infusions. A rare cause of hyperglycemia is neonatal diabetes mellitus, which is discussed separately. (See "Neonatal diabetes mellitus".)

Parenteral administration of glucose — Many preterm or acutely ill neonates receive IV glucose because enteral feeding is insufficient or delayed. Neonatal hyperglycemia often occurs in this setting because of changes in glucose requirements and metabolism. Often, there are multiple factors (eg, sepsis, extreme prematurity, and stress) that affect glucose metabolism and increase the risk of hyperglycemia.

Immediately after birth, IV glucose is typically provided at a rate of 5 to 8 mg/kg per minute to avoid hypoglycemia for neonates who will not be fed enterally. In most settings, sufficient glucose at a rate of 7 mg/kg per minute is provided by the administration of 10 percent dextrose solution at 100 mL/kg per day. Although dextrose is a hydrated form of glucose and is 91 percent glucose, the correction usually is not applied in clinical practice. The glucose infusion rate is increased to approximately 11 to 12 mg/kg per minute in the first two to three days after birth to provide calories for growth. In general, glucose infusion rates >15 mg/kg per minute are avoided, as this exceeds the ability of most infants to oxidize glucose and may promote excessive lipogenesis [5]. (See "Parenteral nutrition in premature infants", section on 'Energy requirements'.)

Additional risk factors associated with hyperglycemia for infants who receive parenteral glucose includes increasing prematurity, intrauterine growth restriction, sepsis, and stress [1,9].

Prematurity — Hyperglycemia during glucose infusion is common in preterm infants and the risk increases with decreasing gestational age [9-12]. Extremely preterm (gestational age <28 weeks) and extremely low birth weight (ELBW; BW <1000 g) infants frequently develop hyperglycemia even in the absence of high rates of glucose infusion [13]. In one prospective study that included 580 EPT neonates, 70 percent experienced hyperglycemia (defined as blood glucose >180 mg/dL [10 mmol/L]) at least once during the first 28 days and nearly half had persistent hyperglycemia for ≥2 days [14].

Proposed underlying mechanisms include reduced insulin secretion, incomplete suppression of hepatic glucose production, defective insulin secretion, and stress response resulting in counter hormone regulation [6]. (See 'Pathogenesis' above.)

Sepsis — Hyperglycemia may be a nonspecific presenting sign of sepsis in an infant with previously normal blood glucose concentrations. Potential mechanisms include the stress response, decreased insulin release, and reduced peripheral utilization of glucose [15]. In the very low birth weight preterm infant (birth weight <1500 g), fungal rather than bacterial sepsis appears to be more commonly associated with hyperglycemia [16].

Stress — The stress response to critical illness with the release of counter regulatory hormones (eg, epinephrine and cortisol) may result in hyperglycemia, especially in preterm infants who require mechanical ventilation. There is limited evidence that increased severity of respiratory distress and metabolic acidosis requiring medical intervention (eg, administration of bicarbonate) is linked to an increased risk of hyperglycemia [1]. The stress response also may be responsible for hyperglycemia occurring after surgery. In this setting, increased rates of fluid administration containing dextrose may also be a contributory factor.

Drugs — Hyperglycemia is a common complication of glucocorticoid therapy, especially in ELBW infants [17]. Hyperglycemia can also occur following administration of methylxanthines [18], phenytoin (the mechanism may be suppression of insulin release or insulin insensitivity) [19] and beta-adrenergic agents (eg, dopamine, epinephrine and norepinephrine) [20]. Hyperglycemia is almost always mild in these cases and does not require therapy. If the infant is on IV fluids, the glucose infusion rate (GIR) can be reduced.

Neonatal diabetes mellitus — Neonatal diabetes mellitus (DM) is a rare cause of hyperglycemia. It is defined as persistent hyperglycemia occurring in the first months of life that lasts more than two weeks and requires insulin for management. Neonatal DM is a monogenic disorder caused by a mutation in genes that encode proteins that affect pancreatic beta cell function.

The etiology, evaluation and management of neonatal DM are discussed separately. (See "Neonatal diabetes mellitus".)

MANAGEMENT — Neonatal hyperglycemia is primarily observed in neonates receiving parenteral glucose infusion, especially preterm infants. As a result, management is focused on reducing blood glucose (BG) levels to target levels while maintaining adequate caloric intake for those patients who are dependent on parenteral nutrition (PN).

Our approach

●Routine monitoring – All patients receiving intravenous (IV) glucose should have routine monitoring of BG levels. For most infants, daily monitoring is sufficient. However, more frequent monitoring is warranted in:

•Extremely low birth weight (ELBW) infants (BW <1000 g)

•Infants with critical illness, sepsis, or other stress

•Infants receiving insulin infusion

●Additional sources of energy intake

•Amino acid and lipid infusion – For infants requiring IV glucose, we suggest administering amino acid solution and lipid emulsion to provide substrate for gluconeogenesis, spare glucose utilization, and stimulate insulin release. Although data are limited, a retrospective study demonstrated that nutritional changes aimed at providing more protein and less fat and carbohydrates resulted in a lower mean blood glucose concentration and less frequent episodes of hyperglycemia without increasing the risk of hypoglycemia [21]. These issues are discussed in greater detail separately. (See "Parenteral nutrition in premature infants".)

•Enteral feeds – Enteral feeding is initiated as soon as possible in order to wean and discontinue PN. Enteral feeds promote the gastric release of glucose-dependent insulinotropic peptide (GIP) and GLP-1, incretin hormones that promote insulin secretion from the pancreas [22,23]. Gastrointestinal incretin-mediated insulin release in response to orogastric administration of a glucose load may occur when a threshold of glucose concentration has exceeded 105 mg/dL. The approach to initiating enteral feeds is discussed separately. (See "Approach to enteral nutrition in the premature infant".)

●Evaluation if hyperglycemia occurs – For neonates who have documented hyperglycemia (ie, BG >180 mg/dL [10 mmol/L), we take the following steps:

•Medications are reviewed and any drugs that may be contributing to hyperglycemia are discontinued, if possible. Examples include glucocorticoids, phenytoin, and beta-adrenergic agents. (See 'Drugs' above.)

•For patients with signs and symptoms of sepsis, blood cultures are obtained and empiric antibiotics are administered, as discussed separately. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation" and "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Empiric antibiotic therapy'.)

●Initial interventions – For patients receiving IV glucose infusions (including PN) who develop hyperglycemia, our approach is as follows:

•For infants with BG >180 to 200 mg/dL (10 to 11.1 mmol/L), the first step is to reduce the glucose infusion rate (GIR) to 4 to 6 mg/kg per minute. This is accomplished by decreasing the dextrose concentration in the fluid. However, a minimum dextrose concentration of 5 percent should be maintained. (See 'Lowering the GIR' below.)

•For neonates with persistent hyperglycemia (BG >200 mg/dL [11.1 mmol/L]) despite reducing the GIR, and for those with poor weight gain because of reduced caloric intake from low GIR, we suggest insulin therapy. (See 'Insulin therapy' below.)

Specific interventions

Lowering the GIR — For neonates receiving IV glucose (including those receiving PN) who have BG levels >180 to 200 mg/dL (10 to 11.1 mmol/L), the first step in management is to decrease the GIR to 4 to 6 mg/kg per minute. This usually successfully lowers the BG level to an acceptable range. In most cases, the GIR is lowered by reducing the concentration of the dextrose in the fluid from 10 to 5 percent. For infants receiving IV glucose in PN, normoglycemia can usually be maintained despite the reduced glucose supply because there are other nutrients that act as a substrate for gluconeogenesis (ie, amino acids and lipids) [24].

However, reducing the GIR is a short-term solution because it results in decreased caloric intake and compromises growth. Glucose tolerance typically improves when enteral feedings are established. (See "Approach to enteral nutrition in the premature infant".)

Insulin therapy — For infants who remain hyperglycemic despite reducing the GIR, we suggest insulin therapy. Insulin improves glucose utilization, reduces blood glucose levels, allows provision of more calories, and promotes growth.

Indications — While indications for insulin therapy are not standardized, most neonatologists, including the authors of this topic, begin insulin therapy in infants who meet either of the following criteria:

●Persistent hyperglycemia (>200 mg/dL [11.1 mmol/L]) despite reduced GIR

●Poor weight gain because of low caloric intake from low GIR

The efficacy and safety of insulin therapy for treating hyperglycemia in preterm neonates is supported by observational studies and a few small clinical trials that were carried out in the 1990s [5,14,25,26]. In a clinical trial involving 24 neonates with hyperglycemia who were randomly assigned insulin therapy or standard care alone, those assigned to insulin therapy tolerated treatment well and had greater energy intake and better weight gain compared with those in the control group [25]. The trial was underpowered to detect differences in other clinical outcomes (mortality or long-term morbidity). In a prospective study that included 80 extremely preterm (EPT) infants who were treated with insulin and 500 EPT infants managed without insulin, insulin therapy was independently associated with lower 70-day mortality after adjusting for confounding factors (odds ratio [OR] 0.34, 95% CI 0.14-0.85) [14].

Dosing and administration

●Dosing and titration – Insulin therapy in neonates consists of regular insulin diluted in normal saline to a concentration of 0.1 units/mL or 0.5 units/mL. Dosing is as follows:

•An initial bolus is given at a dose of 0.05 to 0.1 units/kg IV over 15 minutes.

•The BG level is then monitored every 30 to 60 minutes. (See 'Monitoring' below.)

•If BG remains elevated, the bolus insulin dose can be repeated every four to six hours for up to three doses.

•If the BG remains elevated after three bolus doses of insulin, we suggest continuous infusion of insulin at an initial dose of 0.01 to 0.05 units/kg per hour IV. The infusion rate is adjusted in increments of 0.01 units/kg per hour as needed up to a maximum dose of 0.1 units/kg per hour to maintain BG levels in the target range (150 to <200 mg/dL [8.3 to 11 mmol/L]).

•If BG levels remains <150 mg/dL (8.3 mmol/L), the infusion can be decreased in increments of 0.01 to 0.05 units/kg per hour. The infusion can be discontinued once BG levels are stable at values <150 mg/dL (8.3 mmol/L) on the lowest infusion dose. BG levels should continue to be monitored closely for the next 12 to 24 hours after discontinuing the infusion.

●Administration – Other important aspects of administration of insulin infusions in neonates include:

•Plastic tubing used for infusion should be primed with insulin for at least 20 minutes before treatment because insulin nonspecifically binds to the tubing, resulting in decreased availability to the patient. In one report, recovery of insulin from effluent of primed polyvinyl chloride tubing at a flow rate of 0.2 mL/hour was greater at one, two, four, and eight hours compared with unprimed tubing (42, 85, 91, and 95 versus 22, 38, 67, and 75 percent, respectively) [27].

•The solution should be changed at least every 24 hours or according to the hospital’s pharmacy protocol.

Monitoring — BG levels should be monitored within 30 minutes to 1 hour of the start of the infusion and after any changes in the GIR or insulin infusion. BG should be monitored hourly until stable, and then less frequently.

Target BG range — For most neonates managed with insulin therapy, we suggest a target BG range of 150 to <200 mg/dL (8.3 to <11 mmol/L). We do not aim for tight glycemic control (BG <150 mg/dL [8.3 mmol/L]) since this substantially increases the risk of hypoglycemia without any apparent short- or long-term benefits [28,29].

In a clinical trial of 88 very low birth weight (VLBW) infants who were randomly assigned to tight glycemic control (target BG 70 to 110 mg/dL [4 to 6 mmol/L]) or standard care (target BG 145 to 180 mg/dL [8 to 10 mmol/L]), those assigned to tight glycemic control experienced hypoglycemia (defined as BG <47 mg/dL [2.6 mmol/L]) at a more than two-fold higher rate than those managed with standard care (58 versus 27 percent, respectively) [28]. Mortality rates were similar in both groups (12 versus 9 percent, respectively) as were rates of other neonatal morbidities (eg, sepsis, necrotizing enterocolitis, intraventricular hemorrhage).

Risk of hypoglycemia — In studies of neonates receiving insulin therapy for treatment of hyperglycemia, reported rates of hypoglycemia (typically defined as BG <47 mg/dL [2.6 mmol/L]) range from 0 to 27 percent [28,30-34]. The wide range likely reflects differences in the populations studied (the risk is highest in extremely low birth weight infants) and the method used for detecting hypoglycemia (rates are generally higher in studies using continuous BG monitoring). In addition, the risk of hypoglycemia is considerably higher when insulin is used to treat normoglycemic neonates, as discussed below. (See 'No role for routine early insulin therapy' below.)

For neonates who develop significant hypoglycemia while receiving insulin therapy, management consists of stopping the insulin infusion and administering IV dextrose (2 mL/kg of 10% dextrose in water [D10W] given IV over 5 to 15 minutes). (See "Management and outcome of neonatal hypoglycemia", section on 'IV dextrose infusion'.)

No role for routine early insulin therapy — Routine early use of insulin therapy (ie, administering insulin even in the absence of documented hyperglycemia) has been proposed as a strategy for preventing catabolism, improving glucose control, increasing energy intake, and possibly improving growth in preterm infants. However, based upon the available data, routine insulin therapy does not appear to provide any benefit compared with standard care and it may be harmful [30]. Thus, we suggest the stepwise approach described above and reserve insulin therapy for neonates who have persistent hyperglycemia despite lowering the GIR. (See 'Our approach' above.)

The efficacy and safety of routine early insulin therapy was evaluated in the NIRTURE (Neonatal Insulin Replacement Therapy in Europe) trial, which enrolled 389 very low birth weight (VLBW) infants (BW <1500 g) who were randomly assigned to either early insulin therapy or standard care [30]. Early insulin therapy consisted of a fixed dose of insulin (0.05 units/kg per hour) started within 24 hours of birth and continued until seven days of age; insulin was given in conjunction with IV infusion of 20 percent dextrose as needed to maintain euglycemia. Neonates in the standard care group received insulin only if two consecutive BG levels were >180 mg/dL (10 mmol/L), which occurred in 36 percent of patients. The trial was stopped early because of concerns for potential harm from early insulin therapy. At 28 days, mortality was lower in the standard care group compared with the early insulin group (6 versus 12 percent, respectively; OR 0.45, 95% CI 0.21-0.96). Mortality was also lower in the control group at 40 weeks postmenstrual age, but the difference was not statistically significant (9 versus 14 percent; OR 0.61, 95% CI 0.33-1.15). Episodes of hypoglycemia (defined as BG <47 mg/dL [2.6 mmol/L] for >1 hour) occurred in the early insulin group at a rate that was approximately twice that of the control group (29 versus 17 percent, respectively; OR 2.2, 95% CI 1.34-3.65). Of note, the rate of hypoglycemia in this study was substantially higher than in other studies describing use of insulin in preterm neonates. This is likely explained by NIRTUREꞌs use of continuous glucose monitoring, which has a higher sensitivity for detecting hypoglycemic episodes compared with routine intermittent monitoring. (See 'Risk of hypoglycemia' above.)

OUTCOME — While neonatal hyperglycemia is associated with adverse short- and long-term outcomes, it is unclear if it has a causal role in contributing to morbidity and mortality in this population or if it is merely a marker for disease severity.

●Mortality – Neonatal hyperglycemia is associated with increased mortality risk [10,11,14,35-38]. In a meta-analysis of six observational studies including 1696 preterm neonates, hyperglycemia was associated with a more than two-fold increase in the risk of mortality (adjusted odds ratio [OR] 2.4, 95% CI 1.4-4.0) [38].

●Neurodevelopment outcome – Observational data suggest that neonatal hyperglycemia is associated with increased risk of neurodevelopmental impairment (NDI) [33,38-40]. In the meta-analysis described above, neonatal hyperglycemia was associated with increased risk of severe intraventricular hemorrhage (OR 1.9, 95% CI 1.4-2.5; based on nine studies) and increased risk of long-term disability (OR 2.4, 95% CI 1.5-3.7; based on three studies) [38]. As with mortality, it is unclear whether these associations are causal of if hyperglycemia is merely a marker for disease severity.

Neurodevelopmental outcomes for neonates with hyperglycemia depend largely on the gestational age and other comorbidities. (See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors".)

Further research, including clinical trials to clarify the role of insulin, is needed to provide a better understanding of the consequences of hyperglycemia and determine which infants require intervention.

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – The increased risk of hyperglycemia (defined as glucose levels >125 mg/dL [6.9 mmol/L]) in preterm infants compared with term infants is thought to be due to impaired insulin response, incomplete suppression of hepatic glucose production, and increased secretion of counterregulatory hormones associated with stress. (See 'Pathogenesis' above and 'Definition' above.)

●Causes – The most common cause of neonatal hyperglycemia is administration of intravenous (IV) glucose, especially in very low birth weight (VLBW) infants (BW <1500 g). Other contributing conditions include the stress response to critical illness, sepsis, and drugs associated with hyperglycemia (eg, phenytoin, glucocorticoids, beta-adrenergic agents). A rare cause of neonatal hyperglycemia is neonatal diabetes mellitus, which is discussed separately. (See 'Causes' above and "Neonatal diabetes mellitus".)

●Routine monitoring – All patients receiving IV glucose should have routine monitoring of blood glucose (BG) levels. For most infants, daily monitoring is sufficient. However, more frequent monitoring is warranted in (see 'Our approach' above):

•Extremely low birthweight (ELBW) infants (BW <1000 g)

•Infants with critical illness, sepsis, or other stress

•Infants receiving insulin infusion

●Management – For neonates who have documented hyperglycemia (BG >180 mg/dL [10 mmol/L]), we suggest the following stepwise management approach (see 'Management' above):

•Address potential underlying causes – If possible, drugs that cause hyperglycemia are discontinued. (See 'Drugs' above.)

For patients with signs and symptoms of sepsis, blood cultures are obtained and empiric antibiotics are administered, as discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates" and "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation".)

•Provide additional sources of energy intake – For infants receiving IV glucose through parenteral nutrition (PN), amino acid solution and lipid emulsion are also provided as substrate for gluconeogenesis. Enteral feeding is initiated as soon as possible in order to wean and discontinue PN. These issues are discussed in detail separately. (See "Parenteral nutrition in premature infants" and "Approach to enteral nutrition in the premature infant".)

•Reduce the glucose infusion rate (GIR) – For most neonates with hyperglycemia, we suggest reducing the GIR to 4 to 6 mg/kg per minute as the initial intervention rather than early insulin therapy (Grade 2C). This is accomplished by decreasing the dextrose concentration in the IV fluid or PN solution. However, a minimum dextrose concentration of 5 percent should be maintained. (See 'Lowering the GIR' above.)

•Insulin therapy – For neonates with persistent hyperglycemia (BG >200 mg/dL [11.1 mmol/L]) despite reducing the GIR, and for those with poor weight gain because of reduced caloric intake from low GIR, we suggest insulin therapy (Grade 2C). (See 'Insulin therapy' above.)

-Dosing – Regular insulin is initially administered as a bolus of 0.05 to 0.1 units/kgi IV over 15 minutes. BG levels are then monitored every 30 to 60 minutes. If needed, the bolus dose can be repeated every four to six hours for up to three doses. If the BG remains elevated after three bolus doses of insulin, a continuous insulin infusion is started at an initial dose of 0.01 to 0.05 units/kg per hour IV. (See 'Dosing and administration' above.)

-Monitoring – BG levels should be monitored within 30 minutes to 1 hour of the start of the infusion and after any changes in the GIR or insulin infusion. BG levels should be monitored hourly until stable, and then less frequently. (See 'Monitoring' above.)

-Target BG levels – For most neonates managed with insulin therapy, we suggest a target BG range of 150 to <200 mg/dL (8.3 to <11 mmol/L) rather than aiming for tight glycemic control (BG <150 mg/dL [8.3 mmol/L]) (Grade 2B). (See 'Target BG range' above.)

●Outcome – Neonatal hyperglycemia is associated with increased risk of adverse short- and long-term outcomes; however, it is unclear if it has a causal role in contributing to morbidity and mortality in this population or if it is merely a marker for disease severity. (See 'Outcome' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges See Wai Chan, MD, MPH, who contributed to an earlier version of this topic review.